Structural, nonlinear optical, and molecular docking studies of schiff base compounds as multi-target inhibitors of AChE, BChE, and carbonic anhydrases.

This study investigates the structural, electronic, and inhibitory properties of two novel Schiff base compounds, (E)-5-(((4-bromophenyl)imino)methyl)-2-methoxyphenol (BPhIM) and (E/Z)-5-(((4-aminophenyl)imino)methyl)-2-methoxyphenol (APhIM), as potential multi-target inhibitors of key metabolic enzymes linked to neurodegenerative disorders. The compounds were characterized using density functional theory (DFT) calculations at the B97D3/6-311 + + G(d, p) level. DFT analysis revealed a low energy gap (2.39-2.65 eV), indicating high chemical reactivity, and significant first hyperpolarizability values (9.98-31.25 × 10-30 esu), suggesting strong nonlinear optical (NLO) activity. Molecular electrostatic potential (MEP) maps identified nucleophilic and electrophilic sites, while RDG analysis quantified stabilizing non-covalent interactions. Molecular docking simulations against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase I and II (hCA I/II) demonstrated promising binding affinities. The compounds exhibited excellent predicted inhibition constants (Ki), with APhIM being particularly potent against AChE (Ki = 0.42 µM) and BChE (Ki = 0.83 µM), outperforming the standard drug Tacrine. BPhIM showed strong activity against hCA I (Ki = 0.83 µM). Furthermore, in silico ADMET profiling indicated favorable drug-likeness, high gastrointestinal absorption, and low toxicity risks. The results underscore the dual potential of these Schiff bases as promising scaffolds for the development of NLO materials and as multi-target therapeutic agents, offering a robust basis for future applications in optoelectronics and drug discovery.